N-linked sulfonamides of n-heterocyclic carboxylic acids or carboxylic acid isosteres

ABSTRACT

This invention relates to novel N-linked sulfonamides of N-heterocyclic carboxylic acid and carboxylic acid isosteres, their preparation, and use for treating neurological disorders including physically damaged nerves and neurodegenerative diseases, and for treating alopecia and promoting hair growth.

RELATED APPLICATION DATA

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 60/087,842 to Hamilton et al., entitled “N-LinkedSulfonamides of N-Heterocyclic Carboxylic Acids and Carboxylic AcidIsosteres”, filed Jun. 3, 1998.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to small molecule compounds andcompositions, their preparation and use for treating neurologicaldisorders including physically damaged nerves and neurodegenerativediseases, and for treating alopecia and promoting hair growth.

[0004] 2. Description of the Prior Art

[0005] It has been found that picomolar concentrations of animmunosuppressant such as FK506 and rapamycin stimulate neuriteoutgrowth in PC12 cells and sensory nervous, namely dorsal root ganglioncells (DRGs). Lyons et al., Proc. of Natl. Acad. Sci., 1994 vol. 91, pp.3191-3195. In whole animal experiments, FK506 has been shown tostimulate nerve regeneration following facial nerve injury and resultsin functional recovery in animals with sciatic nerve lesions.

[0006] Several neurotrophic factors effecting specific neuronalpopulations in the central nervous system have been identified. Forexample, it has been hypothesized that Alzheimer's disease results froma decrease or loss of nerve growth factor (NGF). It has thus beenproposed to treat Alzheimer's patients with exogenous nerve growthfactor or other neurotrophic proteins such as brain derived nerve factor(BDNF), glial derived nerve factor, ciliary neurotrophic factor, andneurotropin-3 to increase the survival of degenerating neuronalpopulations.

[0007] Clinical application of these proteins in various neurologicaldisease states is hampered by difficulties in the delivery andbioavailability of large proteins to nervous system targets. Bycontrast, immunosuppressant drugs with neurotrophic activity arerelatively small and display excellent bioavailability and specificity.However, when administered chronically, immunosuppressants exhibit anumber of potentially serious side effects including nephrotoxicity,such as impairment of glomerular filtration and irreversibleinterstitial fibrosis (Kopp et al., 1991, J. Am. Soc. Nephrol. 1:162);neurological deficits, such as involuntary tremors, or non-specificcerebral angina such as non-localized headaches (De Groen et al., 1987,N. Engl. J. Med. 317:861); and vascular hypertension with complicationsresulting therefrom (Kahan et al., 1989 N. Engl. J. Med. 321: 1725).

[0008] Accordingly, there is a need for small-molecule compounds whichare useful for neurotrophic effects and for treating neurodegenerativedisorders.

[0009] Hair loss occurs in a variety of situations. These situationsinclude male pattern alopecia, alopecia senilis, alopecia areata,diseases accompanied by basic skin lesions or tumors, and systematicdisorders such as nutritional disorders and internal secretiondisorders. The mechanisms causing hair loss are very complicated, but insome instances can be attributed to aging, genetic disposition, theactivation of male hormones, the loss of blood supply to hair follicles,and scalp abnormalities.

[0010] The immunosuppressant drugs FK506, rapamycin and cyclosporin arewell known as potent T-cell specific immunosuppressants, and areeffective against graft rejection after organ transplantation. It hasbeen reported that topical, but not oral, application of FK506 (Yamamotoet al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J.Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al.,J. Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in adose-dependent manner. One form of hair loss, alopecia areata, is knownto be associated with autoimmune activities; hence, topicallyadministered immunomodulatory compounds are expected to demonstrateefficacy for treating that type of hair loss. The hair growthstimulating effects of FK506 have been the subject of an internationalpatent filing covering FK506 and structures related thereto for hairgrowth stimulation (Honbo et al., EP 0 423 714 A2). Honbo et al.discloses the use of relatively large tricyclic compounds, known fortheir immunosuppressive effects, as hair revitalizing agents.

[0011] The hair growth and revitalization effects of FK506 and relatedagents are disclosed in many U.S. patents (Goulet et al., U.S. Pat. No.5,258,389; Luly et al., U.S. Pat. No. 5,457,111; Goulet et al., U.S.Pat. No. 5,532,248; Goulet et al., U.S. Pat. No. 5,189,042; and Ok etal., U.S. Pat. No. 5,208,241; Rupprecht et al., U.S. Pat. No. 5,284,840;Organ et al., U.S. Pat. No. 5,284,877). These patents claim FK506related compounds. Although they do not claim methods of hairrevitalization, they disclose the known use of FK506 for effecting hairgrowth. Similar to FK506 (and the claimed variations in the Honbo et al.patent), the compounds claimed in these patents are relatively large.Further, the cited patents relate to immunomodulatory compounds for usein autoimmune related diseases, for which FK506's efficacy is wellknown.

[0012] Other U.S. patents disclose the use of cyclosporin and relatedcompounds for hair revitalization (Hauer et al., U.S. Pat. No.5,342,625; Eberle, U.S. Pat. No. 5,284,826; Hewitt et al., U.S. Pat. No.4,996,193). These patents also relate to compounds useful for treatingautoimmune diseases and cite the known use of cyclosporin and relatedimmunosuppressive compounds for hair growth.

[0013] However, immunosuppressive compounds by definition suppress theimmune system and also exhibit other toxic side effects. Accordingly,there is a need for small molecule compounds which are useful as hairrevitalizing compounds.

SUMMARY OF THE INVENTION

[0014] The present invention relates to the surprising discovery thatN-heterocyclic sulfonamide compounds containing a carboxylic acid orcarboxylic acid isostere moiety may be useful for treatingneurodegenerative disorders and for treating alopecia and promoting hairgrowth. Accordingly, a novel class of sulfonamide derivatives containingan acidic moiety or an isostere thereof attached to the 2-carbon of theN-heterocyclic ring are provided. These compounds stimulate neuronalregeneration and outgrowth and as such are useful for treatingneurological disorders and neurodegenerative diseases. These compoundsalso promote hair growth and as such are useful for treating hair lossdisorders. A preferred feature of the compounds of the present inventionis that they do not exert any significant immunosuppressive activityand/or are non-immunosuppressive.

[0015] A preferred embodiment of this invention is a compound having theformula (I):

[0016] where

[0017] n is 1-3;

[0018] R₁ is selected from the group consisting of hydrogen, C₁-C₉straight or branched chain alkyl, C₂-C₉ straight or branched chainalkenyl, aryl, heteroaryl, carbocycle, or heterocycle;

[0019] D is a bond, or a C₁-C₁₀ straight or branched chain alkyl, C₂-C₁₀alkenyl or C₂-C₁₀ alkynyl;

[0020] R₂ is a carboxylic acid or a carboxylic acid isostere; whereinsaid alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle,or carboxylic acid isostere is optionally substituted with one or moresubstituents selected from R³, where

[0021] R³ is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy,alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano, nitro, imino,alkylamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl,C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl or alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or CO₂R⁴where R⁴ is hydrogen or C₁-C₉ straight or branched chain alkyl oralkenyl;

[0022] or a pharmaceutically acceptable salt, ester or solvate thereof;

[0023] provided that:

[0024] when D is a bond, and R₂ is COOH,

[0025] then R₁ cannot be substituted naphthyl;

[0026] further provided that:

[0027] when D is a bond, and n is 1, and R₂ is COOH or CONHR₃, then R₁is not hydroxyl, methyl, ethyl, substituted or unsubstituted thioethyl,benzothiazole, substituted benzopyran, substituted benzopyrrole,substituted benzoxazole, substituted 5-membered heterocycle containingtwo N and one S heteroatoms, or substituted or unsubstituted phenyl,phenylethyl, naphthyl, pyridyl, thienyl, quinoline, tricyclic ring,aminoethyl, or benzyl;

[0028] further provided that:

[0029] when D is a bond, and n is 2, and R₂ is COOH or phenylbutylester, then R₁ is not substituted phenyl, or a substituted bicyclic ringcontaining two oxygen heteroatoms.

[0030] further provided that:

[0031] when D is a bond, and n is 1-2, and R₂ is a substituted orunsubstituted carbocyclic or heterocyclic ring structure, then R₁ is notsubstituted or unsubstituted carbocycle or heterocycle, or hydroxy;

[0032] further provided that:

[0033] when D is a bond, and n is 1-2, and R₂ is hydroxy, alkoxy,—SO₂(phenyl), N(R₃)₂, substituted thio or alkylthio, —NCO, —PO₃ (Me)₂,or —NCOOC(ethyl)phenyl, then R₁ is not naphthalene, ethylene,substituted tricyclic ring, or substituted or unsubstituted phenyl;

[0034] further provided that:

[0035] when D is C₁-C₃ alkyl or hexenyl, and R₂ is hydroxyl, then R₁ isnot substituted or unsubstituted phenyl, or benzoimidazole;

[0036] further provided that:

[0037] when D is methyl, and n is 1, and R₂ is cyano or COOH, then R1 isnot substituted phenyl;

[0038] further provided that:

[0039] when D is methyl, and n is 1, and R₂ is methoxy or N(R₃)₂, thenR₁ is not methyl, ethyl, phenylethyl, chloro substituted alkyl,substituted oxirane, substituted aziridine wherein one of the carbons isreplaced with an oxygen, substituted or unsubstituted propenyl,substituted phenyl, benzyl, or trifluoro substituted C₂-C₃ alkyl oralkenyl;

[0040] further provided that:

[0041] when D is ethyl, and n is 2, and R₂ is hydroxyl or N(R₃)₂, thenR₁ is not naphthyl;

[0042] further provided that:

[0043] when D is propyl, and n is 1, and R₂ is methoxy, then R₁ is notethylene, cyano substituted ethyl, or triethoxy substituted propyl;

[0044] further provided that:

[0045] when D is not a bond and at least one of D and R₂ contains atleast one S or O, then R₁ is not methyl or substituted phenyl.

[0046] A preferred embodiment of this invention is where R₂ is acarbocycle or heterocycle containing any combination of CH₂, O, S, or Nin any chemically stable oxidation state, where any of the atoms of saidring structure are optionally substituted in one or more positions withR³.

[0047] Especially preferred embodiments of this invention are where R₂is selected from the group below:

[0048] where the atoms of said ring structure may be optionallysubstituted at one or more positions with R³.

[0049] Another preferred embodiment of this invention is where R₂ isselected from the group consisting of —COOH, —SO₃H, —SO₂HNR³, —PO₂(R³)₂,—CN, —PO₃(R³)₂, —OR³, —SR³, —NHCOR³, —N (R³)₂, —CON (R³)₂, —CONH (O) R³,—CONHNHSO₂R³, —COHNSO₂R³, and —CONR³CN.

[0050] Preferred embodiments of this invention are compounds of theformula: (2S)-1-(phenylmethyl)sulfonyl-2-hydroxymethyl pyrrolidine;(2S)-1-(phenylmethyl)sulfonyl-2-pyrrolidinetetrazole;(2S)-1-(phenylmethyl) sulfonyl-2-pyrrolidine carbonitrile; and compounds1-136.

[0051] Another preferred embodiment of this invention is a compositioncontaining: a therapeutically effective amount of a compound of formula(I); a neurotrophic factor different from formula (I); and apharmaceutically suitable carrier.

[0052] Another preferred embodiment of the invention is a method ofpromoting neuronal regeneration and growth in mammals, comprisingadministering to a mammal an effective amount of a N-linked sulfonamideof an N-heterocyclic carboxylic acid or carboxylic acid isostere.

[0053] Another preferred embodiment of the invention is a method oftreating a neurological disorder in an animal, comprising administeringto an animal a therapeutically effective amount of a N-linkedsulfonamide of an N-heterocyclic carboxylic acid or carboxylic acidisostere to stimulate growth of damaged peripheral nerves or to promoteneuronal regeneration.

[0054] Yet another preferred embodiment of the invention is a method ofpreventing neurodegeneration in an animal, comprising administering toan animal an effective amount of an N-linked sulfonamimde of anN-heterocyclic carboxylic acid or carboxylic acid isostere.

[0055] Yet another preferred embodiment of the invention is a method oftreating alopecia or promoting hair growth in an animal, comprisingadministering to an animal an effective amount of an N-linkedsulfonamide of an N-heterocyclic carboxylic acid or carboxylic acidisostere.

BRIEF DESCRIPTION OF THE DRAWINGS

[0056]FIG. 1 is a photograph of C57 Black 6 mice before being shaved forthe hair regeneration experiment.

[0057]FIG. 2 is a photograph of mice treated with a vehicle after sixweeks. FIG. 2 shows that less than 3% of the shaved area is covered withnew hair growth when the vehicle (control) is administered.

[0058]FIG. 3 is a bar graph illustrating relative hair growth on shavedmice treated with N-heterocyclic carboxylic acids or carboxylic acidisosteres at 1 μmole per milliliter three times per week. Hair growthwas evaluated after 14 days of treatment.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[0059] “Alkyl” means a branched or unbranched saturated hydrocarbonchain comprising a designated number of carbon atoms. For example, C₁-C₆straight or branched alkyl hydrocarbon chain contains 1 to 6 carbonatoms, and includes but is not limited to substituents such as methyl,ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl,n-hexyl, and the like. It is also contemplated as within the scope ofthe present invention that “alkyl” may also refer to a hydrocarbon chainwherein any of the carbon atoms of said alkyl are optionally replacedwith O, NH, S, or SO₂. For example, carbon 2 of n-pentyl can be replacedwith O to form propyloxymethyl.

[0060] “Alkenyl” means a branched or unbranched unsaturated hydrocarbonchain comprising a designated number of carbon atoms. For example, C₂-C6straight or branched alkenyl hydrocarbon chain contains 2 to 6 carbonatoms having at least one double bond, and includes but is not limitedto substituents such as ethenyl, propenyl, iso-propenyl, butenyl,iso-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, and the like. It isalso contemplated as within the scope of the present invention that“alkenyl” may also refer to an unsaturated hydrocarbon chain wherein anyof the carbon atoms of said alkenyl are optionally replaced with O, NH,S, or SO₂. For example, carbon 2 of 4-pentene can be replaced with O toform (2-propene)oxymethyl.

[0061] “Alkoxy” means the group -OR wherein R is alkyl as hereindefined. Preferably, R is a branched or unbranched saturated hydrocarbonchain containing 1 to 6 carbon atoms.

[0062] The term “carbocycle” or refers to an organic cyclic moiety inwhich the cyclic skeleton is comprised of only carbon atoms whereas theterm “heterocycle” refers to an organic cyclic moiety in which thecyclic skeleton contains one or more heteroatoms selected from nitrogen,oxygen, or sulfur and which may or may not include carbon atoms.

[0063] Thus, the term “carbocycle” refers to a carbocyclic moietycontaining the indicated number of carbon atoms. The term “C₃-C₈cycloalkyl”, therefore, refers to an organic cyclic substituent in whichthree to eight carbon atoms form a three, four, five, six, seven, oreight-membered ring, including, for example, a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl ring. As usedherein, “carbocycle” may also refer to two or more cyclic ring systemswhich are fused to form, for example bicyclic, tricyclic, or othersimilar bridged substituents (e.g. adamantyl).

[0064] “Aryl” refers to an aromatic carbocyclic group having a singlering, for example a phenyl ring; multiple rings, for example biphenyl;or multiple condensed rings in which at least one ring is aromatic, forexample naphthyl, 1,2,3,4-tetrahydronaphthyl, anthryl, or phenanthryl,which can be unsubstituted or substituted with one or more othersubstituents as defined above. The substituents attached to a phenylring portion of an aryl moiety in the compounds of Formula (I) may beconfigured in the ortho-, meta-, or para- orientations.

[0065] Examples of typical aryl moieties included in the scope of thepresent invention may include, but are not limited to, the following:

[0066] “Aralkyl” refers to alkyl or alkylene (alkenyl) chain which issubstituted with aryl, heteroaryl, carbocycle or heterocycle, oralternatively one or more aryl, heteroaryl, carbocycle, orheterocycle(s) which is/are substituted with alkyl or alkenyl, i.e.‘Alkyl/alkylene which is substituted with Ar’ or ‘Ar which issubstituted with alkyl/alkylene’

[0067] “Heterocycle” refers to a saturated, unsaturated, or aromaticcarbocyclic group having a single ring, multiple rings, or multiplecondensed rings, and having at least one hetero atom such as nitrogen,oxygen, or sulfur within at least one of the rings. “Heteroaryl” refersto a heterocycle in which at least one ring is aromatic. Any of theheterocyclic or heteroaryl groups can be unsubstituted or optionallysubstituted with one or more groups as defined above. Further, bi- ortri-cyclic heteroaryl moieties may comprise at least one ring which iseither completely or partially saturated.

[0068] As one skilled in the art will appreciate, such heterocyclicmoieties may exist in several isomeric forms, all of which areencompassed by the present invention. For example, a 1,3,5-triazinemoiety is isomeric to a 1,2,4-triazine group. Such positional isomersare to be considered within the scope of the present invention.Likewise, the heterocyclic or heteroaryl groups can be bonded to othermoieties in the compounds of the present invention. The point(s) ofattachment to these other moieties is not to be construed as limiting onthe scope of the invention. Thus, by way of example, a pyridyl moietymay be bound to other groups through the 2-, 3-, or 4-position of thepyridyl group. All such configurations are to be construed as within thescope of the present invention.

[0069] Examples of heterocyclic or heteroaryl moieties included in thescope of the present invention may include, but are not limited to, thefollowing:

[0070] “Halo” means at least one fluoro, chloro, bromo, or iodo moiety.

[0071] The term “pharmaceutically acceptable salt, ester, or solvate”refers to salt, ester, or solvates of the subject compounds whichpossess the desired pharmacological activity and which are neitherbiologically nor otherwise undesirable. The salt, ester, or solvates canbe formed with inorganic or organic acids such as acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,hydrochloride hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate,nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate.Base salt, ester, or solvates include ammonium salts, alkali metal saltssuch as lithium, sodium and potassium salts, alkaline earth metal saltssuch as calcium and magnesium salts, salt with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such as arginine, lysine, and so forth. Also, the basicnitrogen-containing groups can be quarternized with such agents as: 1)lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; 2) dialkyl sulfates like dimethyl, diethyl,dibutyl and diamyl sulfates; 3) long chain alkyls such as decyl, lauryl,myristyl and stearyl substituted with one or more halide such aschloride, bromide and iodide; and 4) aryl or arylalkyl halides likebenzyl and phenethyl bromide and others.

[0072] The compounds of this invention may possess at least oneasymmetric center and thus can be produced as mixtures of stereoisomersor as individual enantiomers or diastereomers. The individualstereoisomers may be obtained by using an optically active startingmaterial, by resolving a racemic or non-racemic mixture of anintermediate at some appropriate stage of the synthesis, or byresolution of the compound of formula (I). It is understood that theindividual stereoisomers as well as mixtures (racemic and non-racemic)of stereoisomers are encompassed by the scope of the present invention.The S-stereoisomer at atom 1 of formula I is a most preferred embodimentof the invention.

[0073] “Stereoisomers” are isomers that differ only in the way the atomsare arranged in space.

[0074] “Isomers” are different compounds that have the same molecularformula and includes cyclic isomers such as (iso)indole and otherisomeric forms of cyclic moieties.

[0075] “Enantiomers” are a pair of stereoisomers that arenon-superimposable mirror images of each other.

[0076] “Diastereoisomers” are stereoisomers which are not mirror imagesof each other.

[0077] “Racemic mixture” means a mixture containing equal parts ofindividual enantiomers. “Non-racemic mixture” is a mixture containingunequal parts of individual enantiomers or stereoisomers.

[0078] “Isosteres” are different compounds that have different molecularformulae but exhibit the same or similar properties. For example,tetrazole is an isostere of carboxylic acid because it mimics theproperties of carboxylic acid even though they both have very differentmolecular formulae. Tetrazole is one of many possible isostericreplacements for carboxylic acid. Other carboxylic acid isosterescontemplated by the present invention include

[0079] —COOH, —SO₃H, —SO₂HNR³, —PO₂(R³)₂, —CN, —PO₃(R³)₂, —OR, —SR³,

[0080] —NHCOR³, —N (R³)₂, —CON (R³)₂, —CONH (O) R³, —CONHNHSO₂R³,—COHNSO₂R³, and —CONR³CN.

[0081] In addition, carboxylic acid isosteres can include 5-7 memberedcarbocycles or heterocycles containing any combination of CH₂, O S, or Nin any chemically stable oxidation state, where any of the atoms of saidring structure are optionally substituted in one or more positions. Thefollowing structures are non-limiting examples of preferred carbocyclicand heterocyclic isosteres contemplated by this invention.

[0082] where the atoms of said ring structure may be optionallysubstituted at one or more positions with R³. The present inventioncontemplates that when chemical substituents are added to a carboxylicisostere then the inventive compound retains the properties of acarboxylic isostere. The present invention contemplates that when acarboxylic isostere is optionally substituted with one or more moietiesselected from R³, then the substitution can not eliminate the carboxylicacid isosteric properties of the inventive compound. The presentinvention contemplates that the placement of one or more R³ substituentsupon a carbocyclic or heterocyclic carboxylic acid isostere shall not beat an atom(s) which maintains or is integral to the carboxylic acidisosteric properties of the inventive compound if such a substituent(s)would destroy the carboxylic acid isosteric properties of the inventivecompound.

[0083] Other carboxylic acid isosteres not specifically exemplified ordescribed in this specification are also contemplated by the presentinvention.

[0084] The term “preventing neurodegeneration” as used herein includesthe ability to inhibit or prevent neurodegeneration in patients newlydiagnosed as having a neurodegenerative disease, or at risk ofdeveloping a new degenerative disease and for inhibiting or preventingfurther neurodegeneration in patients who are already suffering from orhave symptoms of a neurodegenerative disease when the compounds aregiven concurrently.

[0085] The term “treatment” as used herein covers any treatment of adisease and/or condition in an animal, particularly a human, andincludes:

[0086] (i) preventing a disease and/or condition from occurring in asubject which may be predisposed to the disease and/or condition but hasnot yet been diagnosed as having it;

[0087] (ii) inhibiting the disease and/or condition, i.e., arresting itsdevelopment; or

[0088] (iii) relieving the disease and/or condition, i.e., causingregression of the disease and/or condition.

[0089] The system used in naming the compounds of the present inventionis shown below, using a compound of formula I as an example.

[0090] A compound of the present invention, especially formula I,wherein n is 1, D is a bond, R₁ is phenylmethyl, and R₂ is —CN, is named(2S)-1-(phenylmethyl) sulfonyl-2-pyrrolidine carbonitrile.

[0091] “Alopecia” refers to deficient hair growth and partial orcomplete loss of hair, including without limitation androgenic alopecia(male pattern baldness), toxic alopecia, alopecia senilis, alopeciaareata, alopecia pelada and trichotillomania. Alopecia results when thepilar cycle is disturbed. The most frequent phenomenon is a shorteningof the hair growth or anagen phase due to cessation of cellproliferation. This results in an early onset of the catagen phase, andconsequently a large number of hairs in the telogen phase during whichthe follicles are detached from the dermal papillae, and the hairs fallout. Alopecia has a number of etiologies, including genetic factors,aging, local and systemic diseases, febrile conditions, mental stresses,hormonal problems, and secondary effects of drugs.

[0092] “Pilar cycle” refers to the life cycle of hair follicles, andincludes three phases:

[0093] (1) the anagen phase, the period of active hair growth which,insofar as scalp hair is concerned, lasts about three to five years;

[0094] (2) the catagen phase, the period when growth stops and thefollicle atrophies which, insofar as scalp hair is concerned, lastsabout one to two weeks; and

[0095] (3) the telogen phase, the rest period when hair progressivelyseparates and finally falls out which, insofar as scalp hair isconcerned, lasts about three to four months.

[0096] Normally 80 to 90 percent of the follicles are in the anagenphase, less than 1 percent being in the catagen phase, and the restbeing in the telogen phase. In the telogen phase, hair is uniform indiameter with a slightly bulbous, non-pigmented root. By contrast, inthe anagen phase, hair has a large colored bulb at its root.

[0097] “Promoting hair growth” refers to maintaining, inducing,stimulating, accelerating, or revitalizing the germination of hair.

[0098] “Treating alopecia” refers to:

[0099] (i) preventing alopecia in an animal which may be predisposed toalopecia; and/or

[0100] (ii) inhibiting, retarding or reducing alopecia; and/or

[0101] (iii) promoting hair growth; and/or

[0102] (iv) prolonging the anagen phase of the hair cycle; and/or

[0103] (v) converting vellus hair to growth as terminal hair. Terminalhair is coarse, pigmented, long hair in which the bulb of the hairfollicle is seated deep in the dermis. Vellus hair, on the other hand,is fine, thin, non-pigmented short hair in which the hair bulb islocated superficially in the dermis. As alopecia progresses, the hairschange from the terminal to the vellus type.

[0104] The term “neurotrophic” as used herein includes withoutlimitation the ability to stimulate neuronal regeneration or growthand/or the ability to prevent or treat neurodegeneration.

[0105] The term “non-immunosuppressive” refers to the inability of thecompounds of the present invention to trigger an immune response whencompared to a control such as FK506 ro cyclosporin A. Assays fordetermining immunosuppression are well known to those of ordinary skillin the art. Specific non-limiting examples of well known assays includePMA and OKT3 assays wherein mitogens are used to stimulate proliferationof human peripheral blood lymphocytes (PBC). Compounds added to suchassay systems are evaluated for their ability to inhibit suchproliferation.

Compounds of the Invention

[0106] The present invention relates to the surprising discovery thatN-linked sulfonamides of N-heterocyclic carboxylic acid or carboxylicacid isostere compounds are neurotrophic and are able to treat alopecia.Accordingly, a novel class of compounds are provided. A preferredfeature of the compounds of the present invention is that they do notexert any significant immunosuppressive activity.

[0107] Preferred compounds of the present invention contain carboxylicacid moieties and other isosteric replacements for carboxylic acidmoieties, of which several examples are specified herein. Otherisosteric replacements for carboxylic acid moieties, known to thoseskilled in the art of medicinal chemistry, are within the scope of theinvention if not otherwise specified.

[0108] The neurotrophic compounds of this invention can be periodicallyadministered to a patient undergoing treatment for neurologicaldisorders or for other reasons in which it is desirable to stimulateneuronal regeneration and growth, such as in various peripheralneuropathic and neurological disorders relating to neurodegeneration.The compounds of this invention can also be administered to mammalsother than humans for treatment of various mammalian neurologicaldisorders.

[0109] The novel compounds of the present invention possess an excellentdegree of neurotrophic activity. This activity is useful in thestimulation of damaged neurons, the promotion of neuronal regeneration,the prevention of neurodegeneration, and in the treatment of severalneurological disorders known to be associated with neuronal degenerationand peripheral neuropathies. The neurological disorders that may betreated include but are not limited to: trigeminal neuralgia,glossopharyngeal neuralgia, Bell's Palsy, myasthenia gravis, musculardystrophy, amyotrophic lateral sclerosis, progressive muscular atrophy,progressive bulbar inherited muscular atrophy, herniated, ruptured orprolapsed invertebrate disk syndromes, cervical spondylosis, plexusdisorders, thoracic outlet destruction syndromes, peripheral neuropathicsuch as those caused by lead, dapsone, ticks, prophyria, orGullain-Barre syndrome, Alzheimer's disease, and Parkinson's disease.

[0110] The above discussion relating to the utility and administrationof the compounds of the present invention also applies to thepharmaceutical compositions of the present invention.

[0111] The term “pharmaceutically acceptable carrier” as used hereinrefers to any carrier, diluent, excipient, suspending agent, lubricatingagent, adjuvant, vehicle, delivery system, emulsifier, disintegrant,absorbent, preservative, surfactant, colorant, flavorant, or sweetener.

[0112] For these purposes the compounds of the present invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir indosage formulations containing conventional non-toxicpharmaceutically-acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous, intravenous,intramuscular, intraperitoneally, intrathecally, intraventricularly,intrasternal and intracranial injection or infusion techniques.

[0113] For oral administration, the compounds of the present inventionmay be provided in any suitable dosage form known in the art. Forexample, the compositions may be incorporated into tablets, powders,granules, beads, chewable lozenges, capsules, liquids, aqueoussuspensions or solutions, or similar dosage forms, using conventionalequipment and techniques known in the art. Tablet dosage forms arepreferred. Tablets may contain carriers such as lactose and corn starch,and/or lubricating agents such as magnesium stearate. Capsules maycontain diluents including lactose and dried corn starch. Aqueoussuspensions may contain emulsifying and suspending agents combined withthe active ingredient.

[0114] When preparing dosage form incorporating the compositions of theinvention, the compounds may also be blended with conventionalexcipients such as binders, including gelatin, pregelatinized starch,and the like; lubricants, such as hydrogenated vegetable oil, stearicacid, and the like; diluents, such as lactose, mannose, and sucrose;disintegrants, such as carboxymethylcellulose and sodium starchglycolate; suspending agents, such as povidone, polyvinyl alcohol, andthe like; absorbents, such as silicon dioxide; preservatives, such asmethylparaben, propylparaben, and sodium benzoate; surfactants, such assodium lauryl sulfate, polysorbate 80, and the like; colorants such asF.D.& C. dyes and lakes; flavorants; and sweeteners.

[0115] Compositions and methods of the invention also may utilizecontrolled release technology. Thus, for example, the inventivecompounds may be incorporated into a hydrophobic polymer matrix forcontrolled release over a period of days. Such controlled release filmsare well known to the art. Particularly preferred are transdermaldelivery systems. Other examples of polymers commonly employed for thispurpose that may be used in the present invention include nondegradableethylene-vinyl acetate copolymer and degradable lactic acid-glycolicacid copolymers which may be used externally or internally. Certainhydrogels such as poly(hydroxyethylmethacrylate) or poly(vinylalcohol)also may be useful, but for shorter release cycles then the otherpolymer releases systems, such as those mentioned above.

[0116] To be effective therapeutically as central nervous systemtargets, the compounds of the present invention should readily penetratethe blood-brain barrier when peripherally administered. Compounds whichcannot penetrate the blood-brain barrier can be effectively administeredby an intraventricular route or other appropriate delivery systemsuitable for administration to the brain.

[0117] The compounds of the present invention may be administered in theform of sterile injectable preparations, for example, as sterileinjectable aqueous or oleaginous suspensions. These suspensions may beformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparations may also be sterile injectable solutions orsuspensions in non-toxic parenterally-acceptable diluents or solvents,for example, as solutions in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as solvents or suspending mediums. For thispurpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids such as oleic acid and its glyceridederivatives, including olive oil and castor oil, especially in theirpolyoxyethylated versions, are useful in the preparation of injectables.These oil solutions or suspensions may also contain long-chain alcoholdiluents or dispersants.

[0118] The compounds of this invention may also be administered rectallyin the form of suppositories. These compositions can be prepared bymixing the drug with a suitable non-irritating excipient which is solidat room temperature, but liquid at rectal temperature and, therefore,will melt in the rectum to release the drug. Such materials includecocoa butter, beeswax and polyethylene glycols.

[0119] The compounds of this invention may also be administeredtopically, especially when the conditions addressed for treatmentinvolve areas or organs readily accessible by topical application,including neurological disorders of the eye, the skin, or the lowerintestinal tract. Suitable topical formulations are readily prepared foreach of these areas.

[0120] For topical application to the eye, or ophthalmic use, thecompounds can be formulated as micronized suspensions in isotonic, pHadjusted sterile saline, or, preferably, as solutions in isotonic, pHadjusted sterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively for the ophthalmic uses thecompounds may be formulated in an ointment such as petrolatum.

[0121] For topical application to the skin, the compounds can beformulated in a suitable ointment containing the compound suspended ordissolved in, for example, a mixture with one or more of the following:mineral oil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the compounds can be formulated in a suitable lotion orcream containing the active compound suspended or dissolved in, forexample, a mixture of one or more of the following: mineral oil,sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and water.

[0122] Topical application for the lower intestinal tract an be effectedin a rectal suppository formulation (see above) or in a suitable enemaformulation.

[0123] Dosage levels on the order of about 0.1 mg to about 10,000 mg ofthe active ingredient compound are useful in the treatment of the aboveconditions, with preferred levels of about 0.1 mg to about 1,000 mg. Theamount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Typically, invitro dosage-effect results provide useful guidance on the proper dosesfor patient administration. Studies in animal models are also helpful.The considerations for determining the proper dose levels are well knownin the art.

[0124] It is understood, however, that a specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, rate of excretion,drug combination, and the severity of the particular disease beingtreated and form of administration.

[0125] To effectively treat alopecia or promote hair growth, thecompounds used in the inventive methods and pharmaceutical compositionsmust readily affect the targeted areas. For these purposes, thecompounds are preferably administered topically to the skin.

[0126] For topical application to the skin, the compounds can beformulated into suitable ointments containing the compounds suspended ordissolved in, for example, mixtures with one or more of the following:mineral oil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the compounds can be formulated into suitable lotions orcreams containing the active compound suspended or dissolved in, forexample, a mixture of one or more of the following: mineral oil,sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and water.

[0127] The compounds can be administered for treatment of hair loss withother hair revitalizing agents. Specific dose levels for the other hairrevitalizing agents will depend upon the factors previously stated andthe effectiveness of the drug combination.

[0128] Other routes of administration known in the pharmaceutical artare also contemplated by this invention.

[0129] Specific embodiments of the inventive compounds are presented inTable I. The present invention contemplates employing the compounds ofTable I, below, for use in compositions and methods to prevent and/ortreat a neurological disorder in an animal, and for use in compositionsand methods to treat alopecia and promote hair growth in an animal, andall other uses suggested in this specification. TABLE I

No. n D R2 R1 1 1 bond COOH Benzyl 2 1 bond COOH α-MethylBenzyl 3 1 bondCOOH 4-MethylBenzyl 4 1 bond Tetrazole Benzyl 5 1 bond SO₃Hα-MethylBenzyl 6 1 CH₂ COOH 4-MethylBenzyl 7 1 bond SO₂HNMe Benzyl 8 1bond CN α-MethylBenzyl 9 1 bond PO₃H₂ 4-MethylBenzyl 10 2 bond COOHBenzyl 11 2 bond COOH α-MethylBenzyl 12 2 bond COOH 4-MethylBenzyl 13 2bond COOH 3,4,5-trimethoxy phenyl 14 2 bond COOH Cyclohexyl 15 2 bondPO₂HEt i-propyl 16 2 bond PO₃HPropyl ethyl 17 2 bond PO₃(Et)₂ Methyl 182 bond OMe tert-butyl 19 2 bond OEt n-pentyl 20 2 bond OPropyl n-hexyl21 1 bond OButyl Cyclohexyl 22 1 bond OPentyl cyclopentyl 23 1 bondOHexyl n-heptyl 24 1 bond SMe n-octyl 25 1 bond SEt n-nonyl 26 2 bondSPropyl 2-indolyl 27 2 bond SButyl 2-furyl 28 2 bond NHCOMe 2-thiazolyl29 2 bond NHCOEt 2-thienyl 30 1 CH₂ N(Me)₂ 2-pyridyl 31 1 (CH₂)₂ N(Me)Etbenzyl 32 1 (CH₂)₃ CON(Me)₂ benzyl 33 1 (CH₂)₄ CONHMe benzyl 34 1 (CH₂)₅CONHEt benzyl 35 1 (CH₂)₆ CONHPropyl 1,1-dimethylpropyl 36 1 bondCONH(O)Me Benzyl 37 1 bond CONH(O)Et α-Methylphenyl 38 1 bondCONH(O)Propyl 4-Methylphenyl 39 2 bond COOH Benzyl 40 2 bond COOHα-Methylphenyl 41 2 bond COOH 4-Methylphenyl 42 1 CH₂ COOH benzyl 43 1(CH₂)₂ COOH benzyl 44 1 (CH₂)₃ COOH benzyl 45 1 (CH₂)₄ COOH benzyl 46 1(CH₂)₅ COOH benzyl 47 1 (CH₂)₆ COOH benzyl 48 1 (CH₂)₇ COOH benzyl 49 1(CH₂)₈ COOH benzyl 50 1 (CH₂)₉ COOH benzyl 51 1 (CH₂)₁₀ COOH benzyl 52 1C₂H₂ COOH benzyl 53 1 2-OH, Et COOH benzyl 54 1 2butylene COOH benzyl 551 i-Pro COOH benzyl 56 1 tert-Bu COOH benzyl 57 1 2-nitro COOH benzylHexyl 58 3 (CH₂)₂ CN benzyl 59 1 (CH₂)₃ CN benzyl 60 3 bond CONHNHSO₂MeBenzyl 61 3 bond CONHNHSO₂Et α-Methylphenyl 62 3 bond CONHSO₂Me4-Methylphenyl 63 2 bond CONHNHSO₂Et Phenyl 64 2 bond CON(Me)CNα-Methylphenyl 65 2 bond CON(Et)CN 4-Methylphenyl 66 1 (CH₂)₂ COOHmethyl 67 1 (CH₂)₃ COOH ethyl 68 1 (CH₂)₄ COOH n-propyl 69 1 (CH₂)₅ COOHt-butyl 70 1 (CH₂)₆ COOH Pentyl 71 1 (CH₂)₇ COOH Hexyl 72 1 (CH₂)₈ COOHSeptyl 73 1 (CH₂)₉ COOH Octyl 74 1 (CH₂)₁₀ COOH Nonyl 75 1 C₂H₂ COOHCyclohexyl 76 1 bond

benzyl 77 1 bond

benzyl 78 1 bond

benzyl 79 1 bond

benzyl 80 1 bond

benzyl 81 1 bond

benzyl 82 1 bond

benzyl 83 1 bond

benzyl 84 1 bond

benzyl 85 1 bond

benzyl 86 1 bond

benzyl 87 1 bond

benzyl 88 1 bond

benzyl 89 1 bond

benzyl 90 1 bond

benzyl 91 1 bond

benzyl 92 1 bond

benzyl 93 1 bond

benzyl 94 1 bond

benzyl 95 1 bond CH₂OH benzyl 96 1 bond CONH₂ benzyl 97 1 bond CN benzyl

[0130] Additional claimed or comparative carboxylic acids and isosteresof N-heterocyclic compounds which also show the remarkable neurotrophicand hair growth effects of the present invention are shown below inTable II: TABLE II

Cpd n D R₂ L R₁ A 1 bond COOH SO₂ Benzyl B 1 bond CONH₂ SO₂ Benzyl C 1bond —CN SO₂ Benzyl D 1 bond tetrazole SO₂ Benzyl E 1 CH₂ —OH SO₂ BenzylF 1 bond COOH 1,2-dioxoethyl 1,1-dimethylpropyl G 2 bond COOH1,2-dioxoethyl 1,1-dimethylpropyl H 1 CH₂ OH 1,2-dioxoethyl1,1-dimethylpropyl I 1 bond tetrazole 1,2-dioxoethyl 1,1-dimethylpropylJ 1 bond —CN 1,2-dioxoethyl 1,1-dimethylpropyl K 2 bond CONH₂1,2-dioxoethyl 1,1-dimethylpropyl where Y and Z are both carbon forcompound A-K, L 1 bond COOH 1,2-dioxoethyl 1,1-dimethylpropyl M 1 bondCOOH 1,2-dioxoethyl 1,1-dimethylpropyl where Z is S for compound H orwhere Y is S for compound I.

Pharmaceutical Compositions of the Present Invention

[0131] The present invention relates to a pharmaceutical compositioncomprising:

[0132] (i) an effective amount of an N-linked sulfonamide ofN-heterocyclic carboxylic acid or carboxylic acid isostere compound; and

[0133] (ii) a pharmaceutically acceptable carrier.

[0134] The present invention also relates to a pharmaceuticalcomposition comprising:

[0135] (i) an effective amount of an N-linked sulfonamide ofN-heterocyclic carboxylic acid or carboxylic acid isostere compound fortreating neurodegenerative diseases, neurological disorders, and nervedamage, or promoting nerve growth in an animal; and

[0136] (ii) a pharmaceutically acceptable carrier.

[0137] The present invention also relates to a pharmaceuticalcomposition comprising:

[0138] (i) an effective amount of an N-linked sulfonamide ofN-heterocyclic carboxylic acid or carboxylic acid isostere compound fortreating alopecia or promoting hair growth in an animal; and

[0139] (ii) a pharmaceutically acceptable carrier.

[0140] Neurotrophic compounds can be administered with otherneurotrophic agents such as neurotrophic growth factor, brain derivedgrowth factor, glial derived growth factor, cilial neurotrophic factor,insulin growth factor and active truncated derivatives thereof, acidicfibroblast growth factor, basic fibroblast growth factor,platelet-derived growth factors, neurotropin-3 and neurotropin 4/5. Thedosage level of other neurotrophic drugs will depend upon the factorspreviously stated and the neurotrophic effectiveness of the drugcombination.

Methods of the Present Invention

[0141] The present invention relates to the use of any of the compoundsseen in Table I and II and other compounds embodied herein, in thepreparation of a medicament for the treatment of a disease such asperipheral neuropathy caused by physical injury or disease state,physical damage to the brain, physical damage to the spinal cord, strokeassociated with brain damage, Alzheimer's Disease, Parkinson's Disease,and amyotrophic lateral sclerosis. The present invention also relates tothe use of carboxylic acid and carboxylic acid isostere compounds fortreating the above-mentioned neuropathies, neurological disorders, andneurological damage.

[0142] The present invention also relates to a method for treatingalopecia or promoting hair growth in an animal, which comprisesadministering to said animal an effective amount of an N-linkedsulfonamide of an N-heterocyclic carboxylic acid or carboxylic acidisostere. The present invention also relates to using the inventivecompounds and compositions in the preparation of a medicament for thetreatment of alopecia or promoting hair growth in an animal.

[0143] The inventive method is particularly useful for treating malepattern alopecia, alopecia senilis, alopecia areata, alopecia resultingfrom skin lesions or tumors, alopecia resulting from cancer therapy suchas chemotherapy and radiation, and alopecia resulting from systematicdisorders such as nutritional disorders and internal secretiondisorders.

[0144] It is understood, however, that a specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, rate of excretion,drug combination, and the severity of the particular disease or disorderbeing treated and form of administration.

MPTP Model of Parkinson's Disease in Mice

[0145] MPTP lesioning of dopaminergic neurons in mice is used as ananimal model of Parkinson's Disease. Four week old male CD1 white miceare dosed i.p. with 30 mg/kg of MPTP for 5 days. Test compounds (4mg/kg), or vehicle, are administered s.c. along with the MPTP for 5days, as well as for an additional 5 days following cessation of MPTPtreatment. At 18 days following MPTP treatment, the animals aresacrificed and the striata dissected and perfusion-fixed. Immunostainingis performed on saggital and coronal brain sections using anti-tyrosinehydroxylase 1 g to quantitate survival and recovery of dopaminergicneurons. In animals treated with MPTP and vehicle, a substantial loss offunctional dopaminergic terminals is observed as compared tonon-lesioned animals. Lesioned animals receiving test compounds show asignificant recovery of TH-stained dopaminergic neurons. This modelpresents quantitation for the recovery of TH-positive dopaminergicneurons in the striatum of animals receiving the compounds of thepresent invention. Table III presents the percent recovery ofdopaminergic neurons in the first (concurrent dosing) paradigm inanimals receiving Compound 1,(2S)-1-[(phenylmethyl)sulfonyl]-2-pyrrolidinecarboxylic acid as wellrelated compounds of the present invention.

[0146] Table III, below, shows the remarkable neuroregenerative effectsof carboxylic acid or carboxylic acid isostere related compoundsillustrating the neurotrophic capability of carboxylic acid isosteres asa class showing that lesioned animals receiving the carboxylic acid orcarboxylic acid isostere compounds provide a remarkable recovery ofTH-stained dopaminergic neurons. TABLE III MPTP Neurodecrenerative Model% Recovery Compound A 24.4% Cmpds B-E ND Compound F 26.7% Compound G NDCompound H 23.2% Compound I 19.6% Compound J 34.1% Compound K 46.5%Compound L 14.0% Compound M ND

[0147] Percent striatal innervation density was quantitated in brainsections with an anti-tyrosine hydroxylase immunoglobulin, which isindicative of functional dopaminergic neurons. The striatal innervationdensity of 23% for animals pretreated with only a vehicle andadministered a vehicle orally during treatment, is indicative of normalnon-lesioned striatal tissue. Striatal innervation density is reduced to5% for animals pretreated with MPTP and administered a vehicle orallyduring treatment, and is indicative of MPTP-induced lesioning.Surprisingly, striatal innervation density is increased 8-13% foranimals pretreated with MPTP and administered 0.4 mg/kg of compoundorally during treatment, indicating substantial neuronal regenerationafter induction of MPTP-derived lesions.

In Vivo Hair Generation Test With C57 Black 6 Mice

[0148] C57 black 6 mice are used to demonstrate the hair revitalizingproperties of the ureas and carbamates of N-heterocyclic carboxylicacids or carboxylic acid isosteres. Referring now to FIGS. 1 and 2 ofthe drawings, C57 black 6 mice, approximately 7 weeks old, had an areaof about 2 inches by 2 inches on their hindquarters shaved to remove allexisting hair. Care was taken not to nick or cause abrasion to theunderlaying dermal layers. The animals were in anagen growth phase, asindicated by the pinkish color of the skin. Referring now to FIG. 2,four animals per group were treated by topical administration with 20%propylene glycol vehicle (FIG. 2), or related compounds dissolved in thevehicle. The animals were treated with vehicle or N-heterocycliccarboxylic acids or isosteres every 48 hours (3 applications total overthe course of 5 days) and the hair growth was allowed to proceed for 6weeks. Hair growth was quantitated by the percent of shaved area coveredby new hair growth during this time period.

[0149]FIG. 2 shows that animals treated with vehicle exhibited only asmall amount of hair growth in patches or tufts, with less than 3% ofthe shaved area covered with new growth.

[0150] In contrast, FIG. 3 shows that animals treated for 2 weeks withthe N-heterocyclic carboxylic acid compounds i.e. compound F, compoundG, and compound K exhibited dramatic hair growth, covering greater than25% of the shaved area in all animals for two of the compounds.

[0151]FIG. 3 shows the relative hair growth on shaven C57 black 6 mice14 days after being treated with N-heterocyclic carboxylic acids orcarboxylic acid isosteres. The mice had a 2×2 inch region on theirbackside shaved to remove all hair. Care was taken not to nick or causeabrasion to the underlying dermal layers. Compounds at a concentrationof 1 μmole per milliliter were carefully applied to the shaved area ofthe mice (5 mice per group) three times per week. Hair growth wasevaluated 14 days after initiation of drug treatment. The relative scalefor assessing hair growth is as follows:

[0152] 0=no growth;

[0153] 1=beginning of growth in small tufts;

[0154] 2=hair growth covering over <25% of shaved area;

[0155] 3=hair growth covering over >25% of shaved area, but less than50% of shaved area;

[0156] 4=hair growth covering over >50% of shaved area, but less than75% of shaved area;

[0157] 5=complete hair growth of shaved area.

[0158] The following examples are illustrative of preferred embodimentsof the invention and are not to be construed as limiting the inventionthereto. All polymer molecular weights are mean average molecularweights. All percentages are based on the percent by weight of the finaldelivery system or formulation prepared unless otherwise indicated andall totals equal 100% by weight.

EXAMPLES

[0159] The inventive compounds may be prepared by a variety of syntheticsequences that utilize established chemical transformations. Anexemplary general pathway to the present compounds is described inScheme I, Scheme II, and Scheme III.

Example 1 Synthesis of (2S)-N- (benzylsulfonyl)-2-pyrrolidinecarboxylicacid (Table I Compound 1) (Table II and Scheme I Compound A)

[0160] To a cooled (0° C.) solution of proline methyl esterhydrochloride salt (5.0 g; 30.19 mmol) in 200 mL of methylene chloridewas added triethylamine (35 mL) and benzenesulfonyl chloride (5.75 g;30.19 mmol). The mixture was stirred for one hour at 0° C. and thenwashed with 2×100 mL of water. The organic phase was dried andconcentrated. Chromatography eluting with 50% EtOAc/hexane delivered8.14 g (5%) of the N-sulfonamide methyl ester, which was dissolved in120 mL of methanol, cooled to 0° C., and treated with 40 mL of 1 Nlithium hydroxide. The mixture was stirred for 1 hour at 0° C. and thenovernight at room temperature. After making the reaction mixture acidic(pH 1) with 1 N Hcl, the product was extracted into metylene chlorideand dried and concentrated to yield 4.25 g of(2S)-N-(benzylsulfonyl)-2-pyrrolidinecarboxylic acid (A) as a whitesolid, ¹H NMR (CDCl₃, 400 MHz): d 1.85-1.90 (m, 2H); 2.08 (m, 1H); 2.18(m, 1H); 3.04 (m, 1H); 3.27 (m, 1H); 4.32-4.35 (m, 2H); 4.45 (m, 1H);4.45 (m, 2H); 7.36 (m, 3H); 7.48 (m, 2H); 10.98 (br, 1H).

Example 2 Synthesis of (2S)-1-(phenylmethylsulfonyl)-2-hydroxymethylpyrrolidine (Compound 95) (Scheme III Compound E).

[0161] To a solution of (S)-(+)-2-pyrrolidinemethyanol (1.01 g, 10 mmol)and triethylamine (1.5 ml, 11 mmol) in 30 ml methylene chloride wasadded 1.9 g (10 mmol) α-toluenesulfonyl chloride at 0° C. with stirring.The reaction was gradually warmed up to room temperature and stirredovernight. The mixture was diluted with water, and extracted into 200 mlmethylene chloride. The organic extract was concentrated and furtherpurified by silica gel to give 1.5 g product as a white solid (58.9%yield). ¹H NMR (CDCl₃): d 01.71-1.88 (m, 4H); 2.05 (br, 1H, OH); 3.22(m, 2H); 3.47 (m 2H); 3.67 (m, 1H); 4.35 (s, 2H); 7.26-7.44 (m, 5H,aromatic).

Example 3 Synthesis of(2S)-1-(phenylmethyl)sulfonyl-2-pyrrolidinecarboxamide (Compound 96)(Scheme II Compound B).

[0162] To a solution of L-prolinamde (2.28 g, 20 mmol) and triethylamine(5.76 ml, 42 mmol) in 40 ml methylene chloride was added 3.92 g (20mmol) α-toluenesulfonyl chloride at 0° C. with stirring. The reactionwas gradually warmed up to room temperature and stirred overnight. Themixture was diluted with water, and extracted into 200 ml methylenechloride. The organic extract was concentrated and further purified bysilica gel to give 3.0 g product as a white solid (55.7% yield). ¹H NMR(CDCl₃): d 01.89 (m, 3H); 2.25 (m, 1H); 3.40 (m, 1H); 3.50 (m, 1H); 3.96(m, 1H); 4.35 (s, 2H); 7.39-7.45 (m, 5H, aromatic).

Example 4 Synthesis of(2S)-1-(phenylmethyl)sulfonyl-2-pyrrolidinecarbonitrile (Compound 97)(Scheme II Compound C).

[0163] To a solution of 0.67 ml DMF (8.7 mmol)in 10 ml acetonitrile at0° C. was added 0.70 ml (8.0 mmol) oxalyl chloride. A white precipitatewas formed immediately and was accompanied by gas evolution. Whencomplete, a solution of 2.0 g (7.5 mmol) of(2S)-1-(phenylmethyl)sulfonyl-2-pyrrolidinecarboxamide in 5.0 mlacetonitrile was added. When the mixture became homogeneous, 1.35 ml(16.5 mmol) pyridine was added. After 5 min., the mixture was dilutedwith water, and extracted by 200 ml ethyl acetate. The organic layer wasconcentrated and further purified by silica gel to give 1.5 g product asa white solid (80% yield). 1H NMR (CDCl₃) : d 01.92 (m, 2H) ; 2.01 (m,1H); 2.11 (m, 1H); 3.45 (m, 2H); 4.35 (s, 2H); 4.65 (m, 1H); 7.26-7.45(m, 5H, aromatic).

Example 5 Synthesis of(2S)-1-(phenylmethyl)sulfonyl-2-pyrrolidinetetrazole (Compound 4)(Scheme II Compound D).

[0164] A mixture of(2S)-1-(phenylmethyl)sulfonyl-2-pyrrolidinecarbonitrile (250 mg, 1mmol), NaN₃ (81 mg, 1.3 mmol) and NH₄Cl (70 mg, 1.3 mmol) in 3 ml DMFwas stirred at 130° C. for 16 hours. The mixture was concentrated andpurified by silica gel to give 120 mg product as a white solid (41.1%yield). ¹H NMR (CDCl₃): d 01.95 (m, 2H); 2.21 (m, 1H); 2.90 (m, 1H);3.40 (m, 2H); 4.27 (s, 2H); 5.04 (m, 1H); 7.36-7.41 (m, 5H, aromatic);8.05 (s, 1H, NH).

Example 6

[0165] A lotion comprising the following composition may be prepared.(%) 95% Ethanol 80.0 an N-linked sulfonamide of N-heterocyclic 10.0carboxylic acid or carboxylic acid isostere α-Tocopherol acetate 0.01Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil purifiedwater 9.0 perfume and dye q. s.

[0166] Into 95% ethanol are added an N-linked sulfonamides ofN-heterocyclic carboxylic acid or carboxylic acid isostere, α-tocopherolacetate, ethylene oxide (40 mole) adducts of hardened castor oil,perfume and a dye. The resulting mixture is stirred and dissolved, andpurified water is added to the mixture to obtain a transparent liquidlotion.

[0167] 5 ml of the lotion may be applied once or twice per day to a sitehaving marked baldness or alopecia.

Example 7

[0168] A lotion comprising the following composition shown may beprepared. (%) 95% Ethanol 80.0 an N-linked sulfonamide of N-heterocyclic0.005 carboxylic acid or carboxylic acid isostere Hinokitol 0.01Ethylene oxide (40 mole) adducts of 0.5 hardened castor oil Purifiedwater 19.0 Perfume and dye q. s.

[0169] Into 95% ethanol are added an N-linked sulfonamides ofN-heterocyclic carboxylic acid or carboxylic acid isostere, hinokitol,ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and adye. The resulting mixture is stirred, and purified water is added tothe mixture to obtain a transparent liquid lotion.

[0170] The lotion may be applied by spraying once to 4 times per day toa site having marked baldness or alopecia.

Example 8

[0171] An emulsion may be prepared from A phase and B phase having thefollowing compositions. (%) (A phase) Whale wax 0.5 Cetanol 2.0Petrolatum 5.0 Squalane 10.0 Polyoxyethylene (10 mole) monostearate 2.0Sorbitan monooleate 1.0 an N-linked sulfonamide of N-heterocyclic 0.01carboxylic acid or carboxylic acid isostere (B phase) Glycerine 10.0Purified water 69.0 Perfume, dye, and preservative q. s.

[0172] The A phase and the B phase are respectively heated and meltedand maintained at 80° C. Both phases are then mixed and cooled understirring to normal temperature to obtain an emulsion.

[0173] The emulsion may be applied by spraying once to 4 times per dayto a site having marked baldness or alopecia.

Example 9

[0174] A cream may be prepared from A phase and B phase having thefollowing compositions. (%) (A Phase) Fluid paraffin 5.0 Cetostearylalcohol 5.5 Petrolaturn 5.5 Glycerine monostearate 33.0 Polyoxyethylene(20 mole) 2-octyldodecyl 3.0 ether Propylparaben 0.3 (B Phase) anN-linked sulfonamide of N-heterocyclic 0.3 carboxylic acid or carboxylicacid isostere Glycerine 7.0 Dipropylene glycol 20.0 Polyethylene glycol4000 5.0 Sodium Hexametaphosphate 0.005 Purified water 44.895

[0175] The A phase is heated and melted, and maintained at 70° C. The Bphase is added into the A phase and the mixture is stirred to obtain anemulsion. The emulsion is then cooled to obtain a cream.

[0176] The cream may be applied once to 4 times per day to a site havingmarked baldness or alopecia.

Example 10

[0177] A liquid comprising the following composition may be prepared.(%) Polyoxyethylene butyl ether 20.0 Ethanol 50.0 an N-linkedsulfonamide of N-heterocyclic 0.001 carboxylic acid or carboxylic acidisostere Propylene glycol 5.0 Polyoxyethylene hardened castor oil 0.4derivative (ethylene oxide 80 mole adducts) Perfume q. s. Purified waterq. s.

[0178] Into ethanol are added polyoxypropylene butyl ether, propyleneglycol, polyoxyethylene hardened castor oil, an N-linked sulfonamide ofN-heterocyclic carboxylic acid or carboxylic acid isostere, and perfume.The resulting mixture is stirred, and purified water is added to themixture to obtain a liquid.

[0179] The liquid may be applied once to 4 times per day to a sitehaving marked baldness or alopecia.

Example 11

[0180] A shampoo comprising the following composition may be prepared.(%) Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0 Betainelauryldimethylaminoacetate 6.0 Ethylene glycol distearate 2.0Polyethylene glycol 5.0 an N-linked sulfonamide of N-heterocyclic 5.0carboxylic acid or carboxylic acid isostere Ethanol 2.0 Perfume 0.3Purified water 69.7

[0181] Into 69.7 of purified water are added 5.0 g of sodiumlaurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betainelauryldimethyl-aminoacetate. Then a mixture obtained by adding 5.0 g ofan N-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylicacid isostere, 5.0 g of polyethylene glycol, and 2.0 g of ethyleneglycol distearate to 2.0 g of ethanol, followed by stirring, and 0.3 gof perfume are successively added. The resulting mixture is heated andsubsequently cooled to obtain a shampoo.

[0182] The shampoo may be used on the scalp once or twice per day.

Example 12

[0183] A patient is suffering from alopecia senilis. An N-linkedsulfonamide of N-heterocyclic carboxylic acid or carboxylic acidisostere, or a pharmaceutical composition comprising the same, may beadministered to the patient. Increased hair growth is expected to occurfollowing treatment.

Example 13

[0184] A patient is suffering from male pattern alopecia. An N-linkedsulfonamide of N-heterocyclic carboxylic acid or carboxylic acidisostere, or a pharmaceutical composition comprising the same may beadministered to the patient. Increased hair growth is expected to occurfollowing treatment.

Example 14

[0185] A patient is suffering from alopecia areata. An N-linkedsulfonamide of N-heterocyclic carboxylic acid or carboxylic acidisostere, or a pharmaceutical composition comprising the same, may beadministered to the patient. Increased hair growth is expected to occurfollowing treatment.

Example 15

[0186] A patient is suffering from hair loss caused by skin lesions. AnN-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylicacid isostere, or a pharmaceutical composition comprising the same, maybe administered to the patient. Increased hair growth is expected tooccur following treatment.

Example 16

[0187] A patient is suffering from hair loss caused by tumors. AnN-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylicacid isostere, or a pharmaceutical composition comprising the same, maybe administered to the patient. Increased hair growth is expected tooccur following treatment.

Example 17

[0188] A patient is suffering from hair loss caused by a systematicdisorder, such as a nutritional disorder or an internal secretiondisorder. An N-linked sulfonamide of N-heterocyclic carboxylic acid orcarboxylic acid isostere, or a pharmaceutical composition comprising thesame, may be administered to the patient. Increased hair growth isexpected to occur following treatment.

Example 18

[0189] A patient is suffering from hair loss caused by chemotherapy. AnN-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylicacid isostere, or a pharmaceutical composition comprising the same, maybe administered to the patient. Increased hair growth is expected tooccur following treatment.

Example 19

[0190] A patient is suffering from hair loss caused by radiation. AnN-linked sulfonamide of N-heterocyclic carboxylic acid or carboxylicacid isostere, or a pharmaceutical composition comprising the same may,be administered to the patient. Increased hair growth is expected tooccur following treatment.

Example 20

[0191] A patient is suffering from a neurodegenerative disease. Acarboxylic acid or carboxylic acid isostere of an N-heterocyclic ring ora pharmaceutical composition comprising the same is administered. Itwould be expected that the patient would improve their condition orrecover.

Example 21

[0192] A patient is suffering from a neurological disorder. A carboxylicacid or carboxylic acid isostere of an N-heterocyclic ring orpharmaceutical compositions comprising same is administered. It would beexpected that the patient would improve their condition or recover.

Example 22

[0193] A patient is suffering from stroke. A carboxylic acid orcarboxylic acid isostere of an N-heterocyclic ring or pharmaceuticalcompositions comprising same is administered. It would be expected thatthe patient would improve their condition or recover.

Example 23

[0194] A patient is suffering from Parkinson's Disease. A carboxylicacid or carboxylic acid isostere of an N-heterocyclic ring orpharmaceutical compositions comprising same is administered. It would beexpected that the patient would improve their condition or recover.

Example 24

[0195] A patient is suffering from Alzheimer's Disease. A carboxylicacid or carboxylic acid isostere of an N-heterocyclic ring orpharmaceutical compositions comprising same is administered. It would beexpected that the patient would improve their condition or recover.

Example 25

[0196] A patient is suffering from a peripheral neuropathy. A carboxylicacid or carboxylic acid isostere of an N-heterocyclic ring orpharmaceutical compositions comprising same is administered. It would beexpected that the patient would improve their condition or recover.

Example 26

[0197] A patient is suffering from amyotrophic lateral sclerosis. Acarboxylic acid or carboxylic acid isostere of an N-heterocyclic ring orpharmaceutical compositions comprising same is administered. It would beexpected that the patient would improve their condition or recover.

Example 27

[0198] A patient is suffering from a spinal injury. A carboxylic acid orcarboxylic acid isostere of an N-heterocyclic ring or pharmaceuticalcompositions comprising same is administered. It would be expected thatthe patient would improve their condition or recover.

Example 28

[0199] A patient is at risk of suffering from a neurodegenerativedisease or neurological disorder. A carboxylic acid or carboxylic acidisostere of an N-heterocyclic ring or a pharmaceutical compositioncomprising the same is prophelactically administered. It would beexpected that the patient would be prevented from some or all of theeffects of the disease or disorder, or would significally improve theircondition or recover over patients who were not pre-treated.

[0200] The invention being thus described, it will be obvious that thesame may be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the invention and all suchmodification are intended to be included within the scope of thefollowing claims.

What is claimed is:
 1. A compound having the formula (I):

where n is 1-3; R₁ is selected from the group consisting of hydrogen,C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chainalkenyl, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or aC₁-C₁₀ straight or branched chain alkyl, C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl; R₂ is a carboxylic acid or a carboxylic acid isostere; whereinsaid alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle,or carboxylic acid isostere is optionally substituted with one or moresubstituents selected from R³, where R³ is hydrogen, hydroxy, halo,haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy,arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, alkylthio, sulfonyl, C₁-C₆ straight or branched chain alkyl,C₂-C₆ straight or branched chain alkenyl or alkynyl, aryl, heteroaryl,carbocycle, heterocycle, or CO₂R⁴ where R⁴ is hydrogen or C₁-C₉ straightor branched chain alkyl or alkenyl; or a pharmaceutically acceptablesalt, ester or solvate thereof; provided that: when D is a bond, and R₂is COOH, then R₁ cannot be substituted naphthyl; further provided that:when D is a bond, and n is 1, and R₂ is COOH or CONHR₃, then R₁ is nothydroxyl, methyl, ethyl, substituted or unsubstituted thioethyl,benzothiazole, substituted benzopyran, substituted benzopyrrole,substituted benzoxazole, substituted 5-membered heterocycle containingtwo N and one S heteroatoms, or substituted or unsubstituted phenyl,phenylethyl, naphthyl, pyridyl, thienyl, quinoline, tricyclic ring,aminoethyl, or benzyl; further provided that: when D is a bond, and n is2, and R₂ is COOH or phenylbutyl ester, then R₁ is not substitutedphenyl, or a substituted bicyclic ring containing two oxygenheteroatoms. further provided that: when D is a bond, and n is 1-2, andR₂ is a substituted or unsubstituted carbocyclic or heterocyclic ringstructure, then R₁ is not substituted or unsubstituted carbocycle orheterocycle, or hydroxy; further provided that: when D is a bond, and nis 1-2, and R₂ is hydroxy, alkoxy, —SO₂(phenyl), N(R₃)₂, substitutedthio or alkylthio, —NCO, —PO₃(Me)₂, or —NCOOC(ethyl)phenyl, then R₁ isnot naphthalene, ethylene, substituted tricyclic ring, or substituted orunsubstituted phenyl; further provided that: when D is C₁-C₃ alkyl orhexenyl, and R₂ is hydroxyl, then R₁ is not substituted or unsubstitutedphenyl, or benzoimidazole; further provided that: when D is methyl, andn is 1, and R₂ is cyano or COOH, then R1 is not substituted phenyl;further provided that: when D is methyl, and n is 1, and R₂ is methoxyor N (R₃)₂, then R₁ is not methyl, ethyl, phenylethyl, chlorosubstituted alkyl, substituted oxirane, substituted aziridine whereinone of the carbons is replaced with an oxygen, substituted orunsubstituted propenyl, substituted phenyl, benzyl, or trifluorosubstituted C₂-C₃ alkyl or alkenyl; further provided that: when D isethyl, and n is 2, and R₂ is hydroxyl or N(R₃)₂, then R₁ is notnaphthyl; further provided that: when D is propyl, and n is 1, and R₂ ismethoxy, then R₁ is not ethylene, cyano substituted ethyl, or triethoxysubstituted propyl; further provided that: when D is not a bond and atleast one of D and R₂ contains at least one S or O, then R₁ is notmethyl or substituted phenyl.
 2. The compound of claim 1, wherein R₂ isa carbocycle or heterocycle containing any combination of CH₂, O, S, orN in any chemically stable oxidation state, wherein any of the atoms ofsaid ring structure are optionally substituted in one or more positionswith R³.
 3. The compound of claim 1, wherein R₂ is selected from thefollowing group:

where the atoms of said ring structure may be optionally substituted atone or more positions with R³.
 4. The compound of claim 1, wherein thecarboxylic acid or carboxylic acid isostere of R₂ is selected from thegroup consisting of: —COOH, —SO₃H, —SO₂HNR³, —PO₂(R³)₂, —CN, —PO₃(R³) ₂,—OR³, —SR³, —NHCOR³, —N (R³)₂, —CON (R³)₂, —CONH(O)R³, —CONHNHSO₂R³,—COHNSO₂R³, and —CONR³CN.
 5. The compounds,(2S)-1-(phenylmethyl)sulfonyl-2-hydroxymethyl pyrrolidine;(2S)-1-(phenylmethyl)sulfonyl-2-pyrrolidinetetrazole.
 6. Apharmaceutical composition, comprising: a) an effective amount of anN-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylicacid isostere; and b) a pharmaceutically acceptable carrier.
 7. Thepharmaceutical composition of claim 6, wherein the N-linked sulfonamideof N-heterocyclic carboxylic acid or carboxylic acid isostere comprisesa compound of formula (I):

where n is 1-3; R₁ is selected from the group consisting of hydrogen,C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chainalkenyl, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or aC₁-C₁₀ straight or branched chain alkyl, C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl; R₂ is a carboxylic acid or a carboxylic acid isostere; whereinsaid alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle,or carboxylic acid isostere is optionally substituted with one or moresubstituents selected from R³, where R³ is hydrogen, hydroxy, halo,haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy,arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, alkylthio, sulfonyl, C₁-C₆ straight or branched chain alkyl,C₂-C₆ straight or branched chain alkenyl or alkynyl, aryl, heteroaryl,carbocycle, heterocycle, or CO₂R⁴ where R⁴ is hydrogen or C₁-C₉ straightor branched chain alkyl or alkenyl; or a pharmaceutically acceptablesalt, ester or solvate thereof.
 8. The pharmaceutical composition ofclaim 7, wherein R₂ is a carbocycle or heterocycle containing anycombination of CH₂, O, S, or N in any chemically stable oxidation state,wherein any of the atoms of said ring structure are optionallysubstituted in one or more positions with R³.
 9. The pharmaceuticalcomposition of claim 7, wherein R₂ is selected from the following group:

where the atoms of said ring structure may be optionally substituted atone or more positions with R³.
 10. The pharmaceutical composition ofclaim 7, wherein R₂ is selected from the group consisting of: —COOH,—SO₃H, —SO₂HNR³, —PO₂(R³)₂, —CN, —PO₃(R³)₂, —OR³, —SR³, —NHCOR³,—N(R³)₂, —CON(R³)₂, —CONH(O)R³, —CONHNHSO₂R³, —COHNSO₂R³, and —CONR³CN.11. The pharmaceutical composition of claim 7, wherein the N-linkedsulfonamide of an N-heterocyclic carboxylic acid compound is selectedfrom the group consisting of compounds 1-97.
 12. The pharmaceuticalcomposition of claim 6, further comprising a neurotrophic factordifferent from formula (I).
 13. The pharmaceutical composition of claim12, wherein said neurotrophic factor different from formula (I) isselected from neurotrophic growth factor, brain derived growth factor,glial derived growth factor, cilial neurotrophic factor, insulin growthfactor and active truncated derivatives thereof, acidic fibroblastgrowth factor, basic fibroblast growth factor, platelet-derived growthfactors, neurotropin-3 and neurotropin 4/5.
 14. A method of treating aneurological disorder in an animal, comprising: administering to theanimal an effective amount of an N-linked sulfonamide of anN-heterocyclic carboxylic acid or carboxylic acid isostere to stimulategrowth of damaged peripheral nerves or to promote neuronal regeneration.15. The method of claim 14, wherein the neurological disorder isselected from the group consisting of peripheral neuropathies cause byphysical injury or disease state, physical damage to the brain, physicaldamage to the spinal cord, stroke associated with brain damage, andneurological disorders relating to neurodegeneration.
 16. The method ofclaim 14, wherein the neurological disorder is selected from the groupconsisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophiclateral sclerosis.
 17. The method of claim 14, wherein the neurologicaldisorder is Alzheimer's disease.
 18. The method of claim 14, wherein theneurological disorder is Parkinson's disease.
 19. The method of claim14, wherein the neurological disorder is amyotrophic lateral sclerosis.20. The method of claim 14, wherein the N-linked sulfonamide of anN-heterocyclic carboxylic acid or carboxylic acid isostere isnon-immunosuppressive.
 21. The method of claim 14, wherein the N-linkedsulfonamide of an N-heterocyclic carboxylic acid or carboxylic acidisostere comprises a compound of formula (I):

where n is 1-3; R₁ is selected from the group consisting of hydrogen,C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chainalkenyl, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or aC₁-C₁₀ straight or branched chain alkyl, C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl; R₂ is a carboxylic acid or a carboxylic acid isostere; whereinsaid alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle,or carboxylic acid isostere is optionally substituted with one or moresubstituents selected from R³, where R³ is hydrogen, hydroxy, halo,haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy,arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, alkylthio, sulfonyl, C₁-C₆ straight or branched chain alkyl,C₂-C₆ straight or branched chain alkenyl or alkynyl, aryl, heteroaryl,carbocycle, heterocycle, or CO₂R⁴ where R⁴ is hydrogen or C₁-C₉ straightor branched chain alkyl or alkenyl; or a pharmaceutically acceptablesalt, ester or solvate thereof.
 22. The method of claim 21, wherein R₂is a carbocycle or heterocycle containing any combination of CH₂, O, S,or N in any chemically stable oxidation state, wherein any of the atomsof said ring structure are optionally substituted in one or morepositions with R³.
 23. The method of claim 21, wherein R₂ is selectedfrom the following group:

where the atoms of said ring structure may be optionally substituted atone or more positions with R³.
 24. The method of claim 21, wherein R₂ isselected from the group consisting of: —COOH, —SO₃H, —SO₂HNR³,—PO₂(R³)₂, —CN, —PO₃(R³)₂, —OR^(3, —SR) ³, —NHCOR³, —N(R³)₂, —CON(R³)₂,—CONH(O)R³, —CONHNHSO₂R³, —COHNSO₂R³, and —CONR³CN.
 25. The method ofclaim 14, wherein the N-linked sulfonamide of an N-heterocycliccarboxylic acid compound is selected from the group consisting ofcompounds 1-97.
 26. The method of claim 14, further comprisingadministering a neurotrophic factor different from formula (I).
 27. Themethod of claim 26, wherein said neurotrophic factor different fromformula (I) is selected from the group consisting of neurotrophic growthfactor, brain derived growth factor, glial derived growth factor, cilialneurotrophic factor, insulin growth factor and active truncatedderivatives thereof, acidic fibroblast growth factor, basic fibroblastgrowth factor, platelet-derived growth factors, neurotropin-3, andneurotropin 4/5.
 28. A method of stimulating growth of damagedperipheral nerves, comprising: administering to damaged peripheralnerves a therapeutically effective amount of an N-linked sulfonamide ofan N-heterocyclic carboxylic acid or carboxylic acid isostere tostimulate or promote growth of the damaged peripheral nerves.
 29. Themethod of claim 28, wherein the N-linked sulfonamide of anN-heterocyclic carboxylic acid or carboxylic acid isostere isnon-immunosuppressive.
 30. The method of claim 28, wherein the N-linkedsulfonamide of an N-heterocyclic carboxylic acid or carboxylic acidisostere comprises a compound of formula (I):

where n is 1-3; R₁ is selected from the group consisting of hydrogen,C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chainalkenyl, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or aC₁-C₁₀ straight or branched chain alkyl, C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl; R₂ is a carboxylic acid or a carboxylic acid isostere; whereinsaid alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle,or carboxylic acid isostere is optionally substituted with one or moresubstituents selected from R³, where R³ is hydrogen, hydroxy, halo,haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy,arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, alkylthio, sulfonyl, C₁-C₆ straight or branched chain alkyl,C₂-C₆ straight or branched chain alkenyl or alkynyl, aryl, heteroaryl,carbocycle, heterocycle, or CO₂R⁴ where R⁴ is hydrogen or C₁-C₉ straightor branched chain alkyl or alkenyl; or a pharmaceutically acceptablesalt, ester or solvate thereof.
 31. The method of claim 30, wherein R₂is a carbocycle or heterocycle containing any combination of CH₂, O, S,or N in any chemically stable oxidation state, wherein any of the atomsof said ring structure are optionally substituted in one or morepositions with R³.
 32. The method of claim 30, wherein R₂ is selectedfrom the following group:

where the atoms of said ring structure may be optionally substituted atone or more positions with R³.
 33. The method of claim 30, wherein R₂ isselected from the group consisting of: —COOH, —SO₃H, —SO₂HNR³,—PO₂(R³)₂, —CN, —PO₃(R³)₂, —OR³, —SR³, —NHCOR³, —N(R³)₂, —CON(R³)₂,—CONH(O)R³, —CONHNHSO₂R³, —COHNSO₂R³, and —CONR³CN.
 34. The method ofclaim 28, wherein the N-linked sulfonamide of an N-heterocycliccarboxylic acid compound is selected from the group consisting ofcompounds 1-97.
 35. The method of claim 28, further comprisingadministering a neurotrophic factor different from formula (I).
 36. Themethod of claim 35, wherein said neurotrophic factor different fromformula (I) is selected from the group consisting of neurotrophic growthfactor, brain derived growth factor, glial derived growth factor, cilialneurotrophic factor, insulin growth factor and active truncatedderivatives thereof, acidic fibroblast growth factor, basic fibroblastgrowth factor, platelet-derived growth factors, neurotropin-3, andneurotropin 4/5.
 37. A method for promoting neuronal regeneration andgrowth in animals, comprising: administering to an animal atherapeutically effective amount of a neurotrophic N-linked sulfonamideof an N-heterocyclic carboxylic acid or carboxylic acid isostere topromote neuronal regeneration.
 38. The method of claim 37, wherein theN-linked sulfonamide of an N-heterocyclic carboxylic acid or carboxylicacid isostere is non-immunosuppressive.
 39. The method of claim 37,wherein the N-linked sulfonamide of an N-heterocyclic carboxylic acid orcarboxylic acid isostere comprises a compound of formula (I):

where n is 1-3; R₁ is selected from the group consisting of hydrogen,C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chainalkenyl, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or aC₁-C₁₀ straight or branched chain alkyl, C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl; R₂ is a carboxylic acid or a carboxylic acid isostere; whereinsaid alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle,or carboxylic acid isostere is optionally substituted with one or moresubstituents selected from R³ , where R³ is hydrogen, hydroxy, halo,haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy,arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, alkylthio, sulfonyl, C₁-C₆ straight or branched chain alkyl,C₂-C₆ straight or branched chain alkenyl or alkynyl, aryl, heteroaryl,carbocycle, heterocycle, or CO₂R⁴ where R⁴ is hydrogen or C₁-C₉ straightor branched chain alkyl or alkenyl; or a pharmaceutically acceptablesalt, ester or solvate thereof.
 40. The method of claim 39, wherein R₂is a carbocycle or heterocycle containing any combination of CH₂, O, S,or N in any chemically stable oxidation state, wherein any of the atomsof said ring structure are optionally substituted in one or morepositions with R³.
 41. The method of claim 39, wherein R₂ is selectedfrom the following group:

where the atoms of said ring structure may be optionally substituted atone or more positions with R³.
 42. The method of claim 39, wherein R₂ isselected from the group consisting of: —COOH, —SO₃H, —SO₂HNR³,—PO₂(R³)₂, —CN, —PO₃(R³)₂, —OR³, —SR³, —NHCOR³, —N(R³)₂, —CON(R³)₂,—CONH(O)R³, —CONHNHSO₂R³, —COHNSO₂R³, and —CONR³CN.
 43. The method ofclaim 37, wherein the N-linked sulfonamide of an N-heterocycliccarboxylic acid compound is selected from the group consisting ofcompounds 1-97.
 44. The method of claim 37, further comprisingadministering a neurotrophic factor different from formula (I).
 45. Themethod of claim 44, wherein said neurotrophic factor different fromformula (I) is selected from the group consisting of neurotrophic growthfactor, brain derived growth factor, glial derived growth factor, cilialneurotrophic factor, insulin growth factor and active truncatedderivatives thereof, acidic fibroblast growth factor, basic fibroblastgrowth factor, platelet-derived growth factors, neurotropin-3, andneurotropin 4/5.
 46. A method for preventing neurodegeneration in ananimal, comprising: administering to an animal a therapeuticallyeffective amount of a neurotrophic N-linked sulfonamide of anN-heterocyclic carboxylic acid or carboxylic acid isostere to preventneurodegeneration.
 47. The method of claim 46, wherein theneurodegeneration is Alzheimer's disease.
 48. The method of claim 46,wherein the neurodegeneration is Parkinson's disease.
 49. The method ofclaim 46, wherein the neurodegeneration is amyotrophic lateralsclerosis.
 50. The method of claim 46, wherein the N-linked sulfonamideof an N-heterocyclic carboxylic acid or carboxylic acid isostere isnon-immunosuppressive.
 51. The method of claim 46, wherein the N-linkedsulfonamide of an N-heterocyclic carboxylic acid or carboxylic acidisostere comprises a compound of formula (I):

where n is 1-3; R₁ is selected from the group consisting of hydrogen,C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chainalkenyl, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or aC₁-C₁₀ straight or branched chain alkyl, C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl; R₂ is a carboxylic acid or a carboxylic acid isostere; whereinsaid alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle,or carboxylic acid isostere is optionally substituted with one or moresubstituents selected from R³, where R³ is hydrogen, hydroxy, halo,haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy,arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, alkylthio, sulfonyl, C₁-C₆ straight or branched chain alkyl,C₂-C₆ straight or branched chain alkenyl or alkynyl, aryl, heteroaryl,carbocycle, heterocycle, or CO₂R⁴ where R⁴ is hydrogen or C₁-C₉ straightor branched chain alkyl or alkenyl; or a pharmaceutically acceptablesalt, ester or solvate thereof.
 52. The method of claim 51, wherein R₂is a carbocycle or heterocycle containing any combination of CH₂, O, S,or N in any chemically stable oxidation state, wherein any of the atomsof said ring structure are optionally substituted in one or morepositions with R³.
 53. The method of claim 51, wherein R₂ is selectedfrom the following group:

where the atoms of said ring structure may be optionally substituted atone or more positions with R³.
 54. The method of claim 51, wherein R₂ isselected from the group consisting of: —COOH, —SO₃H, —SO₂HNR³, —PO₂(R³)₂, —CN, —PO₃(R³)₂, —OR³, —SR³, —NHCOR³, —N(R³)₂, —CON(R³)₂,—CONH(O)R³, —CONHNHSO₂R³, —COHNSO₂R³, and —CONR³CN.
 55. The method ofclaim 46, wherein the N-linked sulfonamide of an N-heterocycliccarboxylic acid compound is selected from the group consisting ofcompounds 1-97.
 56. The method of claim 46, further comprisingadministering a neurotrophic factor different from formula (I).
 57. Themethod of claim 56, wherein said neurotrophic factor different fromformula (I) is selected from the group consisting of neurotrophic growthfactor, brain derived growth factor, glial derived growth factor, cilialneurotrophic factor, insulin growth factor and active truncatedderivatives thereof, acidic fibroblast growth factor, basic fibroblastgrowth factor, platelet-derived growth factors, neurotropin-3, andneurotropin 4/5.
 58. A method for treating alopecia or promoting hairgrowth in an animal, which comprises administering to said animal aneffective amount of an N-linked sulfonamide of an N-heterocycliccarboxylic acid or carboxylic acid isostere.
 59. The method of claim 58,wherein the N-linked sulfonamide of an N-heterocyclic carboxylic acid orcarboxylic acid isostere is non-immunosuppressive.
 60. The method ofclaim 58, wherein the N-linked sulfonamide of an N-heterocycliccarboxylic acid or carboxylic acid isostere is a compound of formula(I):

where n is 1-3; R₁ is selected from the group consisting of hydrogen,C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chainalkenyl, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or aC₁-C₁₀ straight or branched chain alkyl, C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl; R₂ is a carboxylic acid or a carboxylic acid isostere; whereinsaid alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle,or carboxylic acid isostere is optionally substituted with one or moresubstituents selected from R³, where R³ is hydrogen, hydroxy, halo,haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy,arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, alkylthio, sulfonyl, C₁-C₆ straight or branched chain alkyl,C₂-C₆ straight or branched chain alkenyl or alkynyl, aryl, heteroaryl,carbocycle, heterocycle, or CO₂R⁴ where R⁴ is hydrogen or C₁-C₉ straightor branched chain alkyl or alkenyl; or a pharmaceutically acceptablesalt, ester or solvate thereof.
 61. The method of claim 60, wherein R₂is a carbocycle or heterocycle containing any combination of CH₂, O, S,or N in any chemically stable oxidation state, wherein any of the atomsof said ring structure are optionally substituted in one or morepositions with R³.
 62. The method of claim 60, wherein R₂ is selectedfrom the following group:

where the atoms of said ring structure may be optionally substituted atone or more positions with R³.
 63. The method of claim 60, wherein R₂ isselected from the group consisting of —COOH, —SO₃H, —SO₂HNR³, —PO₂(R³)₂,—CN, —PO₃(R³)₂, —OR³, —SR³, —NHCOR³, —N(R³)₂, —CON(R³)₂, —CONH(O)R³,—CONHNHSO₂R³, —COHNSO₂R³, and —CONR³CN.
 64. The method of claim 58,wherein the carboxylic acid or carboxylic acid isostere is selected fromthe group consisting of compounds 1-97.
 65. A pharmaceutical compositioncomprising: (i) an effective amount of a N-linked sulfonamide of anN-heterocyclic carboxylic acid or carboxylic acid isostere for treatingalopecia or promoting hair growth in an animal; and (ii) apharmaceutically acceptable carrier.
 66. The pharmaceutical compositionof claim 65, wherein the N-linked sulfonamide of an N-heterocycliccarboxylic acid or carboxylic acid isostere is non-immunosuppressive.67. The composition of claim 65, wherein the carboxylic acid orcarboxylic acid isostere is a compound of formula (I):

where n is 1-3; R₁ is selected from the group consisting of hydrogen,C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chainalkenyl, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or aC₁-C₁₀ straight or branched chain alkyl, C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl; R₂ is a carboxylic acid or a carboxylic acid isostere; whereinsaid alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle,or carboxylic acid isostere is optionally substituted with one or moresubstituents selected from R³, where R³ is hydrogen, hydroxy, halo,haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy,arylalkyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, alkylthio, sulfonyl, C₁-C₆ straight or branched chain alkyl,C₂-C₆ straight or branched chain alkenyl or alkynyl, aryl, heteroaryl,carbocycle, heterocycle, or CO₂R⁴ where R⁴ is hydrogen or C₁-C₉ straightor branched chain alkyl or alkenyl; or a pharmaceutically acceptablesalt, ester or solvate thereof.
 68. The composition of claim 67, whereinR₂ is a carbocycle or heterocycle containing any combination of CH₂, O,S, or N in any chemically stable oxidation state, wherein any of theatoms of said ring structure are optionally substituted in one or morepositions with R³.
 69. The composition of claim 67, wherein R₂ isselected from the following group:

where the atoms of said ring structure may be optionally substituted atone or more positions with R³.
 70. The composition of claim 67, whereinR₂ is selected from the group consisting of: —COOH, —SO₃H, —SO₂HNR³,—PO₂(R³)₂, —CN, —PO₃(R³)₂, —OR³, —SR₃, —NHCOR³, —N(R³)₂, —CON(R³)₂,—CONH (O)R³, —CONHNHSO₂R³, —COHNSO₂R³, and —CONR³CN.
 71. The compositionof claim 65, wherein the carboxylic acid or carboxylic acid isostere isselected from the group consisting of compounds 1-97.